Previously, we have shown that ASK1-interacting protein 1 (AIP1, also known as DAB2IP), a novel member of the Ras-GAP (Ras-GTPase-activating protein) protein family, opens its conformation in response to tumor necrosis factor (TNF), allowing it to form a complex with TRAF2-ASK1 that leads to activation of ASK1-JNK/p38 signaling in endothelial cells (EC). In the present study, we show that a TNF-inducible 14-3-3-binding site on AIP1 is critical for the opening of its conformation and for the AIP1-mediated TNF signaling. Ser-604, located in the C-terminal domain of AIP1, was identified as a 14-3-3-binding site. TNF treatment of EC induces phosphorylation of AIP1 at Ser-604 as detected by a phospho-specific antibody, with a similar kinetics to ASK1-JNK/p38 activation. 14-3-3 associates with an open, active state of AIP1 assessed by an in vitro pulldown assay. Mutation of AIP1 at Ser-604 (AIP1-S604A) blocks TNF-induced complex formation of AIP1 with 14-3-3. TNF treatment normally induces association of AIP1 with TRAF2-ASK1. The interactions with TRAF2 and ASK1 do not occur with AIP1-S604A, suggesting that phosphorylation at this site not only creates a 14-3-3-binding site but also opens up AIP1, allowing binding to TRAF2 and ASK1. Overexpression of AIP1-S604A blocks TNF-induced ASK1-JNK activation. We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC. Furthermore, RIP1 synergizes with AIP1 (but not AIP1-S604A) in inducing both JNK/p38 activation and EC apoptosis. Our results demonstrate that RIP1-mediated AIP1 phosphorylation at the 14-3-3-binding site Ser-604 is essential for TNF-induced TRAF2-RIP1-AIP1-ASK1 complex formation and for the activation of ASK1-JNK/p38 apoptotic signaling.

Iron-mediated oxidative stress has been recognized as one of the leading causes of chronic kidney injury. The effect of L-type calcium channel (LTCC) blocker on iron overload has been shown in cardiomyocytes, liver cells, and nerve cells. So far, few studies have examined whether blockers improve kidney iron-mediated oxidative stress. Yet, the precise mechanism through which blockers regulate kidney iron transport still remains unclear. In the present work, treatment with nifedipine or verapamil decreased oxidative stress and reduced the cell apoptosis-induced by ferric ammonium citrate (P < 0.05), decreased cellular iron contents, and prevented the rising of iron level-induced by ferric ammonium citrate (P > 0.05) in HK-2 and HEK293 cells. Besides, nifedipine and verapamil treatments increased the expression of divalent metal transporter 1, divalent metal transporter ZIP14, and ferroportin1 in HK-2 cells and increased ferroportin1 expression in HEK293 cells. In summary, LTCC blockers alleviate iron overload-induced oxidative stress in renal epithelial cells by blocking the iron uptake and enhancing cellular iron transport and/or iron export, thus synergistically reducing the cellular iron accumulation. Consequently, LTCC blockers may be used as a novel treatment for the prevention of primary or secondary iron overload-kidney injury.

Paclitaxel, a compound that targets microtubules in cancer cells and inhibits mitosis, has been used as a first-line treatment for recurrent or metastatic breast cancer for over three decades. Research into paclitaxel resistance has yielded thousands of articles. However, this body of research has not been analyzed systematically and quantitatively. This study employs bibliometric analysis and visualisation techniques using VOSviewer and CiteSpace software to elucidate the contributions from countries and institutions, collaboration patterns, journal publication trends, research evolution, and current hotspots. Our findings reveal that leading research institutions in the United States, Europe, and East Asia hold significant advantages in this field. Specifically, the United States contributed the most to this field, with MD Anderson Cancer Center being the most prominent research institution and having a broad collaboration network. Prestigious oncology journals serve as primary platforms for disseminating key findings, with Cancer Research publishing the most relevant articles and having the highest co-citation frequency. We identified the main research branches by analysing keyword co-occurrence and keyword bursts, including treatment methods, drug delivery, mechanisms, and cellular response. Current research focuses on unveiling resistance mechanisms and exploring new therapeutic strategies. Paclitaxel resistance in breast cancer, particularly in TNBC and metastatic cases, remains an active and critical research area. Integrating nanotechnology into drug development and therapeutic strategies is a current focal point and promises to be a significant future direction. These insights highlight a strategic direction for future research, including strengthening international partnerships, deepening understanding of resistance mechanisms, and applying engineered therapeutics for targeted breast cancer treatments.

Breast cancer is a highly heterogeneous malignancy with multiple molecular subtypes and variable treatment responses. Despite advances in endocrine therapy, HER2-targeted therapy, chemotherapy, and immunotherapy, treatment resistance and disease recurrence remain major clinical challenges. There is growing evidence that transcriptional plasticity and enhancer relinking contribute to tumor progression and treatment adaptation, highlighting the powerful role of epigenetic regulators. CREB-binding protein (CBP) and E1A-associated protein p300 (EP300) are transcriptional coactivators that regulate breast cancer enhancer activity and lineage-specific gene expression. Emerging research suggests that CBP/p300 is more of a context-dependent vulnerability point than a universal carcinogenic driver. ER-positive tumors exhibit a strong dependence on CBP/p300-mediated transcriptional programs, while the triple-negative breast cancer subgroup, including androgen receptor-positive and immunosuppressive tumors, may rely on CBP/p300-dependent signaling to maintain survival and treatment resistance. This is in contrast to their role in HER2-positive breast cancer. This review summarizes the biological functions of CBP/p300 in breast cancer and discusses subtype-specific vulnerability, biomarker-directed patient stratification, drug resistance mechanisms, rational combination strategies, and current translational challenges, emphasizing the need for precise treatment of breast cancer.

Background: Postsurgical distant metastasis remains the leading cause of breast cancer-related mortality, yet reliable biomarkers for identifying patients at high risk of recurrence are lacking. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and tumor-associated macrophages (TAMs) contribute to an immunosuppressive tumor microenvironment; however, their combined prognostic value in breast cancer metastasis has not been defined. Methods: TNFAIP3 and M2 macrophage markers (CD163 and CD206) were assessed by immunohistochemistry in 96 breast cancer surgical specimens, including 48 metastatic and 48 non-metastatic cases. Expression patterns were validated using 1,085 breast cancer samples from the GEPIA2 database. Functional studies were performed using TNFAIP3-overexpression and TNFAIP3-knockdown breast cancer cell models co-cultured with macrophages. Macrophage polarization, cytokine production, and tumor cell migration and invasion were analyzed by flow cytometry, qPCR, ELISA, and Transwell assays. Predictive performance was evaluated using multivariate logistic regression and receiver operating characteristic (ROC) analyses. Results: TNFAIP3 expression was positively correlated with CD163 ( r = 0.322, P < 0.001) and CD206 ( r = 0.370, P < 0.001) in breast tumors developing postoperative distant metastasis, with stronger correlations observed in the GEPIA2 cohort. Mechanistically, TNFAIP3 overexpression promoted CCL2 secretion, activated CCR2 signaling, and induced M2-like macrophage polarization, resulting in a 1.5- to 2.3-fold increase in tumor cell migration and invasion. Elevated TNFAIP3, CD163, and CD206 were independently associated with metastasis. TNFAIP3 alone showed good predictive performance (AUC = 0.84), while the combination of TNFAIP3 and CD163 achieved the highest accuracy (AUC = 0.90), followed by TNFAIP3 and CD206 (AUC = 0.87). Conclusions: TNFAIP3 promotes macrophage reprogramming through the CCL2/CCR2 axis, fostering a pro-metastatic tumor microenvironment in breast cancer. Combined assessment of TNFAIP3 and M2 macrophage markers provides a novel biomarker panel for postsurgical risk stratification and prognosis of metastatic relapse, supporting further prospective clinical validation.